ArticleNature chemistry2015
A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1.
Article in Nature chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 33 citations in OpenAlex.
- Targeting a Pleckstrin Homology Domain with a Lysine-Reactive Covalent Binder.Journal of medicinal chemistry · 2026Article
- Click Reactions in Kinetic Target-Guided Synthesis: Progress in the Discovery of Inhibitors for Biological Targets.Methods and protocols · 2026Review
- Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition.The journal of physical chemistry. B · 2025Article
- Stereochemical engineering yields a multifunctional peptide macrocycle inhibitor of Akt2 by fine-tuning macrocycle-cell membrane interactions.Communications chemistry · 2023Article
- Protein Catalyzed Capture (PCC) Agents for Antigen Targeting.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Copper-ligand clusters dictate size of cyclized peptide formed during alkyne-azide cycloaddition on solid support.RSC advances · 2021Article
- Protein-Catalyzed Capture Agents.Chemical reviews · 2019Review
- PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling.Nature chemical biology · 2019Article
- Ribosome-Templated Azide-Alkyne Cycloadditions Using Resistant Bacteria as Reaction Vessels:ACS medicinal chemistry letters · 2018Article
- Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity.Scientific reports · 2017Article
- Degradation of Akt using protein-catalyzed capture agents.Journal of peptide science : an official publication of the European Peptide Society · 2016Article
- Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry.Journal of the American Chemical Society · 2016Article
- Supramolecular Probes for Assessing Glutamine Uptake Enable Semi-Quantitative Metabolic Models in Single Cells.Journal of the American Chemical Society · 2016Article
- A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands.Angewandte Chemie (International ed. in English) · 2015Article
- Epitope targeting of tertiary protein structure enables target-guided synthesis of a potent in-cell inhibitor of botulinum neurotoxin.Angewandte Chemie (International ed. in English) · 2015Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.